DESCRIPTION: Applicant's Abstract The overall goal of these studies is to determine the mechanism(s) underlying morphine-induced immunosuppression and to further examine the factors contributing to an increased immune sensitivity following repetitive morphine exposure to stress. Specifically, the experiments in this proposal will test the hypotheses that the inhibition of immune cell activities by morphine: 1) is mediated through several discrete central nuclei which modulate the activity of the paraventricular nucleus (PVN) of the hypothalamus; 2) is peripherally mediated through stimulation of sympathetic neuronal outflow and/or alteration of circulating cytokine levels; 3) produces an apparent 'tolerant' state which is accompanied by an increased immune sensitivity to stress or drug withdrawal. The specific aims which will test these hypotheses include: Aim # 1: Determine the central pathways involved in morphine-induced suppression of immune cell function. It is hypothesized that morphine suppresses lymphocyte responses by modulating the autonomic outflow from the PVN from multiple sites in the brain, including the periaqueductal gray (PAG), dorsal raphe nucleus (DR), bed nucleus of the stria terminalis (BNST) and the anterior hypothalamus (AH). These studies will 1) establish the site specificity for morphine in the regulation of immune cell activity for each of these areas, 2) pharmaco-logically characterize the opioid receptor involved, 3) evaluate the role of the PVN as a coordinator of opioid-induced immune cell alterations and 4) begin to evaluate the interactions of opioids with other neurotransmitter systems utilized by these selected tissues which innervate the PVN. Aim #2: Identify the peripheral mechanisms involved in central opioid receptor modulation of immune responses. An underlying hypothesis of these studies is that the suppression of lymphocyte proliferation following morphine is mediated through opioid stimulation of the autonomic nervous system (ANS). To more definitively test this hypothesis, these studies will examine the effects of 1) lesioning descending neuronal output, 2) neuronal stimulating selective target peripheral tissues and 3) increasing IL-6 and potentially other cytoyines on morphine-induced changes in immune cell activity. Aim #3: Examine mechanisms contributing to the increased sensitivity of morphine-tolerant rats to the immunosuppressive effects of stress. These studies will test the hypothesis that the prolonged stimulation of adrenal secretion of glucocorticoids and/or the activity of the ANS, which accompany chronic morphine administration, results in an increased vulnerability of the immune system to exposure to stress and spontaneous withdrawal of drug. The fact that intravenous drug users represent a major risk group for ANS makes it imperative to understand the central action and peripheral mechanisms by which abusive drugs and stress interact to modulate the immune system.